The P2X7 receptor tracer [11C]SMW139 as an in vivo marker of neuroinflammation in multiple sclerosis: a first-in man study.

PURPOSE: The novel PET tracer [11C]SMW139 binds with high affinity to the P2X7 receptor, which is expressed on pro-inflammatory microglia. The purposes of this first in-man study were to characterise pharmacokinetics of [11C]SMW139 in patients with active relapsing remitting multiple sclerosis (RRMS) and healthy controls (HC) and to evaluate its potential to identify in vivo neuroinflammation in RRMS. METHODS: Five RRMS patients and 5 age-matched HC underwent 90-min dynamic [11C]SMW139 PET scans, with online continuous and manual arterial sampling to generate a metabolite-corrected arterial plasma input function. Tissue time activity curves were fitted to single- and two-tissue compartment models, and the model that provided the best fits was determined using the Akaike information criterion. RESULTS: The optimal model for describing [11C]SMW139 kinetics in both RRMS and HC was a reversible two-tissue compartment model with blood volume parameter and with the dissociation rate k4 fixed to the whole-brain value. Exploratory group level comparisons demonstrated an increased volume of distribution (VT) and binding potential (BPND) in RRMS compared with HC in normal appearing brain regions. BPND in MS lesions was decreased compared with non-lesional white matter, and a further decrease was observed in gadolinium-enhancing lesions. In contrast, increased VT was observed in enhancing lesions, possibly resulting from disruption of the blood-brain barrier in active MS lesions. In addition, there was a high correlation between parameters obtained from 60- to 90-min datasets, although analyses using 60-min data led to a slight underestimation in regional VT and BPND values. CONCLUSIONS: This first in-man study demonstrated that uptake of [11C]SMW139 can be quantified with PET using BPND as a measure for specific binding in healthy controls and RRMS patients. Additional studies are warranted for further clinical evaluation of this novel neuroinflammation tracer.

In vivo assessment of neuroinflammation in progressive multiple sclerosis: a proof of concept study with [18F]DPA714 PET.

BACKGROUND: Over the past decades, positron emission tomography (PET) imaging has become an increasingly useful research modality in the field of multiple sclerosis (MS) research, as PET can visualise molecular processes, such as neuroinflammation, in vivo. The second generation PET radioligand [18F]DPA714 binds with high affinity to the 18-kDa translocator-protein (TSPO), which is mainly expressed on activated microglia. The aim of this proof of concept study was to evaluate this in vivo marker of neuroinflammation in primary and secondary progressive MS. METHODS: All subjects were genotyped for the rs6971 polymorphism within the TSPO gene, and low-affinity binders were excluded from participation in this study. Eight patients with progressive MS and seven age and genetic binding status matched healthy controls underwent a 60 min dynamic PET scan using [18F]DPA714, including both continuous on-line and manual arterial blood sampling to obtain metabolite-corrected arterial plasma input functions. RESULTS: The optimal model for quantification of [18F]DPA714 kinetics was a reversible two-tissue compartment model with additional blood volume parameter. For genetic high-affinity binders, a clear increase in binding potential was observed in patients with MS compared with age-matched controls. For both high and medium affinity binders, a further increase in binding potential was observed in T2 white matter lesions compared with non-lesional white matter. Volume of distribution, however, did not differentiate patients from healthy controls, as the large non-displaceable compartment of [18F]DPA714 masks its relatively small specific signal. CONCLUSION: The TSPO radioligand [18F]DPA714 can reliably identify increased focal and diffuse neuroinflammation in progressive MS when using plasma input-derived binding potential, but observed differences were predominantly visible in high-affinity binders.

Three-Tesla MRI does not improve the diagnosis of multiple sclerosis: A multicenter study.

OBJECTIVE: In the work-up of patients presenting with a clinically isolated syndrome (CIS), 3T MRI might offer a higher lesion detection than 1.5T, but it remains unclear whether this affects the fulfilment of the diagnostic criteria for multiple sclerosis (MS). METHODS: We recruited 66 patients with CIS within 6 months from symptom onset and 26 healthy controls in 6 MS centers. All participants underwent 1.5T and 3T brain and spinal cord MRI at baseline according to local optimized protocols and the MAGNIMS guidelines. Patients who had not converted to MS during follow-up received repeat brain MRI at 3-6 months and 12-15 months. The number of lesions per anatomical region was scored by 3 raters in consensus. Criteria for dissemination in space (DIS) and dissemination in time (DIT) were determined according to the 2017 revisions of the McDonald criteria. RESULTS: Three-Tesla MRI detected 15% more T2 brain lesions compared to 1.5T (p < 0.001), which was driven by an increase in baseline detection of periventricular (12%, p = 0.015), (juxta)cortical (21%, p = 0.005), and deep white matter lesions (21%, p < 0.001). The detection rate of spinal cord lesions and gadolinium-enhancing lesions did not differ between field strengths. Three-Tesla MRI did not lead to a higher number of patients fulfilling the criteria for DIS or DIT, or subsequent diagnosis of MS, at any of the 3 time points. CONCLUSION: Scanning at 3T does not influence the diagnosis of MS according to McDonald diagnostic criteria.

Cerebrospinal Venous Outflow in Multiple Sclerosis Patients versus Fatigue and/or Depression.

BACKGROUND: Endovascular treatment of impaired cerebrospinal venous outflow has been suggested to improve the overall quality of life in multiple sclerosis (MS) patients. Fatigue and depression are key factors in measuring the quality of life in MS patients. OBJECTIVE: In the present study, we investigated the correlation between anomalous venous outflow and the seriousness of fatigue and depression in MS patients and healthy controls. METHODS: Five cerebrospinal venous outflow parameters were measured in 20 MS patients and age- and sex-matched controls using extra- and transcranial Colour Doppler sonography. All patients and volunteers filled out the Fatigue Severity Scale (FSS) and Hospital Anxiety Depression Subscale (HADS). RESULTS: Nine abnormal parameters were found in 8 MS patients, whereas five abnormal parameters were found in 3 healthy controls (no significant difference). Only 1 MS patient met the criteria for chronic cerebrospinal venous insufficiency compared to 2 healthy controls. No significant differences were found in the FSS and HADS scores between patients with and without abnormal cerebrospinal venous outflow parameters. CONCLUSIONS: We found no significantly impaired cerebrospinal venous outflow in patients with MS versus sex- and age-matched controls. Furthermore, we did not find any correlation between anxiety or depression and impaired venous outflow in MS patients.